570 Biowissenschaften; Biologie
Gegenstand dieser Veröfffentlichung ist eine Reimplementierung des TSNI (Time Series Network Identification)-Tools zur Rekonstruktion von genregulatorischen Netzwerken aus Zeitserien von Gen-Expressionsprofilen. Das auf gewöhnlichen Differentialgleichungen basierende Tool wurde algorithmisch verbessert und an die Verarbeitung großer Datensätze angepasst. Durch Ausschöpfung des Potentials moderner Multi-CPU und GPU-Architekturen wurden die erforderlichen Berechnungen erheblich beschleunigt. Bei der Überführung des mit Matlab implementierten Tools in die Programmiersprache C wurde zudem die Bedienbarkeit verbessert.
Durch Einsatz der GPU-beschleunigten Mathematik-Bibliothek MAGMA konnten unter Verwendung eines normalen Desktop-Rechners Leistungssteigerungen um das 18,7-fache bei 11.000 Genen verzeichnet werden. Darüber hinaus rekonstruierte das verbesserte TSNI weitaus mehr biologisch richtige Beziehungen als vergleichbare Anwendungen.
Carcinogenesis is a complex multifactorial, multistage process, but the precise mechanisms are not well understood. In this study, we performed a genome-wide analysis of the copy number variation (CNV), breakpoint region (BPR) and fragile sites in 2,737 tumor samples from eight tumor entities and in 432 normal samples. CNV detection and BPR identification revealed that BPRs tended to accumulate in specific genomic regions in tumor samples whereas being dispersed genome-wide in the normal samples. Hotspots were observed, at which segments with similar alteration in copy number were overlapped along with BPRs adjacently clustered. Evaluation of BPR occurrence frequency showed that at least one was detected in about and more than 15% of samples for each tumor entity while BPRs were maximal in 12% of the normal samples. 127 of 2,716 tumor-relevant BPRs (termed ‘common BPRs’) exhibited also a noticeable occurrence frequency in the normal samples. Colocalization assessment identified 20,077 CNV-affecting genes and 169 of these being known tumor-related genes. The most noteworthy genes are KIAA0513 important for immunologic, synaptic and apoptotic signal pathways, intergenic non-coding RNA RP11-115C21.2 possibly acting as oncogene or tumor suppressor by changing the structure of chromatin, and ADAM32 likely importance in cancer cell proliferation and progression by ectodomain-shedding of diverse growth factors, and the well-known tumor suppressor gene p53. The BPR distributions indicate that CNV mutations are likely non-random in tumor genomes. The marked recurrence of BPRs at specific regions supports common progression mechanisms in tumors. The presence of hotspots together with common BPRs, despite its small group size, imply a relation between fragile sites and cancer-gene alteration. Our data further suggest that both protein-coding and non-coding genes possessing a range of biological functions might play a causative or functional role in tumor biology. This research enhances our understanding of the mechanisms for tumorigenesis and progression.